Treatment of migraine headache with diffusion of toxin in non-muscle related areas of the mouth

ABSTRACT

A method for treating a patient with migraine headache includes administering to the patient a therapeutically effective amount of an invertebrate presynaptic neurotoxin in a pharmaceutically safe form. The administration includes intra-oral extramuscular injection of the neurotoxin in a foramina of the sphenopalatine ganglion for enabling diffusion of the neurotoxin to the ganglion with the administration being on the trigeminal cervical system, enabling axonal transport of the neurotoxin from distal to central sites.

Botulinum toxins have been used to treat chronic migraine. This is well established in the art. By way of example only, see U.S. Pat. Nos. 5,714,468, 5,721,215, 6,458,365, 7,655,244, 7,704,511, and 7,981,433. All of these references are to be incorporated herewith in their entirety. These patents include: Binder; Botulinum toxin injections to the head for migraine, Blumenfeld; Botulinum toxin injections to the sphenopalatine ganglion, nasal approach and vascular approach, suture line technique (these are not foramina or exit points); Aoki; Tension type headache treatment with Botulinum toxin, and Turkel; 31 sites as for the FDA approved protocol for chronic migraine.

Heretofore, onabotulinumtoxinA has been FDA approved for treatment of migraine headache. The dose used is 155 to 195 units, with a dilution of 2 cc per 100 units of onabotulinumtoxinA. Doses ranging from 25 units to 260 units have been used to treat various headache disorders. These have involved intra-muscular injections in fixed sites and follow the pain sites.

Botulinum toxin side effects are usually due to local diffusion to surrounding muscles producing unwanted weakness.

SUMMARY OF THE INVENTION

In general, a method for treating a patient with migraine headache in accordance with the present invention includes administering to the patient a therapeutically effective amount of an invertebrate presynaptic neurotoxin in a pharmaceutically safe form. The administration includes intra-oral extramuscular injection of the neurotoxin in a foramina of the sphenopalatine ganglion for enabling diffusion of the neurotoxin to the ganglion; and the administration being on the trigeminal cervical system, enabling axonal transport of the neurotoxin from distal to central sites.

In general, the present invention aims to minimize any side effects present with prior injection techniques and uses a novel injection approach to achieve this goal. In addition, this invention aims to increase the efficacy across multiple headache types including chronic and episodic migraine, post-traumatic headache, post-craniotomy headache, tension type headache and medication overuse headache. This invention focuses the medication on the sites of maximal benefit; i.e., the trigemino-cervical nerves and the sphenopalatine ganglion nerves.

The technique involves administration to allow for maximizing the dose and thus the effect on the trigeminal cervical system and sphenopalatine ganglion system; while minimizing any side effects.

This invention uses the same methods of administration described in the procedures above to deliver endotoxins to the same sites. Endotoxins do not cause muscle weakness as they are targeted to sensory nerves, however the current technique of intra-muscular injections can still cause side effects related to needle trauma of muscle and the need to do multiple injections.

More specifically, the administration includes the extramuscular injection of diluted Botulinum toxin. Still more particularly, the Botulinum toxins may be Botulinum toxin A, B, C, D, E, F, and G. Alternatively, the neurotoxin may include an endotoxin such as, for example, when the endotoxin is an endopeptidase derived from Botulinum toxin.

BRIEF DESCRIPTION OF THE DRAWINGS

The advantages and features of the present invention will be better understood by the following description when considered in conjunction with the accompanying drawings, in which:

FIG. 1 is a diagram of injection sites in accordance with the present invention; and refers specifically to the greater and lesser palatine foramen 20, which are nerve exit points for the palatine nerve and the incisive foramen 30, a nerve exit point for the nasopalatine nerve.

DETAILED DESCRIPTION

In general, dilute Botulinum toxin: about 1 cc per 100 units, is injected in the sphenopalatine ganglion, allowing the toxin to diffuse into distal sensory nerve endings (there is no muscle in this location). Alternatively, the toxin is injected in a foramina of the sphenopalatine ganglion. No muscle weakness results as all the injections are in non-muscular regions.

Intra-oral injections are done in the region of the foramina of the sphenopalatine ganglion. This allows diffusion of toxin to the ganglion without a deep injection through muscle. Thus, lower doses can be used. There is no risk of muscle trauma including intra-muscular hemorrhage related to needles tracking through muscle to reach the sphenopalatine ganglion. The dilution for these injections is about 1 cc per 100 units of Botulinum toxin, to prevent diffusion to other intra-oral structures. See FIG. 1.

There are two possible intra-oral approaches to the sphenopalatine ganglion. See FIG. 1. The first intraoral method involves needle insertion in the region of the mucobuccal fold (not shown) at the maxillary second molar and advancing the needle in a posterior, superior, and medial direction, into the region of the pterygopalatine fossa. The second intra-oral approach to the sphenopalatine ganglion 20 is through the greater palatine canal. The opening of this is located between the middle of the second molar and the middle of the third molar. This site will be approximately 7 mm from the end of the hard palate.

CLINICAL EXAMPLES Case 1

43 year old woman, with a long standing history of migraine, suffers with headache on twenty (20) days out of each month and requires triptan medication on twelve (12) days out of each month to control her more disabling headaches. She meets criteria for chronic migraine complicated by medication overuse headache. She fails to respond to numerous preventive medications such as Topiramate and Propranolol. She is treated with onabotulinumtoxinA using the PREEMPT injection protocol with fixed sites and follow-the-pain injections. Total dose given 195 units. She develops neck pain, brow ptosis and no improvement in her headache frequency after three (3) treatment cycles.

She is then successfully treated with the injection protocol as outlined in this invention using OnabotulinumtoxinA diluted as follows: 100 units in 1 cc of normal saline. The injections are done with a 1 inch 30 gauge needle attached to a 1 cc syringe. The needle is inserted at 45 degrees angling the needle posteriorly, medially and superiorly with the entry point at the mucobuccal fold adjacent to the left maxillary second molar. 45 units are injected in the region of the left sphenopalatine ganglion and 45 units in a similar fashion in the region of the right sphenopalatine ganglion; for a total dose of 90 units. The patient does not develop neck weakness or pain as the neck musculature is not injected and the patient does not develop brow ptosis as the frontalis muscle is not injected.

Case 2

38 year old man presents with a long history of frequent episodic migraines. He averages 10-14 headache days per month. His headaches are side locked and only involve the right peri-orbital region. He works as a magician. He does not wish to use any medications that might interfere with his concentration, dexterity or facial expressions. As a result he is a poor candidate for oral preventive medications such as topiramate which can cause cognitive slowing, amitriptyline which can cause drowsiness, and Botox using the PREEMPT protocol as this could result in some loss of facial expression due to injections of the frontalis, corrugators and procerus muscles. He is successfully treated using the method of administration of onabotulinumtoxinA outlined in this invention, as follows:

100 units of OnabotulinumtoxinA is diluted with 1 cc of normal saline. The patient is lying with the head tilted far backwards and the mouth wide open so that the palate of the mouth is fully visible. A 27 gauge needle, 1.5 inches long is inserted 7 mm posterior to the edge of the hard palate in between the second and third molars angling upwards. 25 units is delivered in the region of the sphenopalatine ganglion bilaterally for a total of 50 units. The needle is inserted deep to the hard palate limiting any palatal weakness. The patient has no loss of facial expression from the delivery of onabotulinumtoxinA in this method.

Lower dosing of onabotulinumtoxinA is used as the medication is delivered in a focus where it will have the most benefit; i.e.: no unnecessary flooding of medication to unwanted sites.

The present invention may suitably comprise, consist of, or consist essentially of the recited elements. Further, the invention illustratively disclosed herein suitably may be practiced in the absence of any element which is not specifically disclosed herein. Accordingly, any and all modifications, variations or equivalent arrangements which may occur to those skilled in the art, should be considered to be within the scope of the present invention as defined in the appended claims. 

What is claimed is:
 1. A method for treating a human patient with migraine headache, said method comprising: administering to the patient a therapeutically effective amount of a diluted Botulinum toxin in a pharmaceutically safe form; the administration comprising intra-oral extramuscular injection of the Botulinum toxin in a foramina of the sphenopalatine ganglion without deep needle administration, for enabling diffusion of the Botulinum toxin to the ganglion; and the administration being on the trigeminal cervical system, enabling axonal transport of the Botulinum toxin from distal to central sites.
 2. (canceled)
 3. The method according to claim 1 wherein the Botulinum toxin is Botulinum Toxin A.
 4. The method according to claim 1 wherein the diluted Botulinum toxin is about 1 cc normal saline per 100 units of Botulinum toxin.
 5. The method according to claim 1 wherein the Botulinum toxin comprises an Endotoxin obtained from Botulinum toxin.
 6. The method of claim 5 wherein the Endotoxin is an endopeptidase obtained from Botulinum toxin.
 7. The method of claim 1, wherein administering comprises injecting Botulinum toxin into one or more of the greater palatine foramen, the lesser palatine foramen and the incisive foramen.
 8. The method according to claim 1 wherein the Botulinum toxin is Botulinum Toxin B.
 9. The method of claim 3 wherein the Botulium toxin A is onabotulinumtoxin A.
 10. A method for treating a human patient with migraine headache, said method comprising administering to the patient a therapeutically effective amount of diluted Botulinum toxin in a pharmaceutically safe form; the administration comprising intra-oral extramuscular injection into one or more of the greater palatine foramen, the lesser palatine foramen and the incisive foramen.
 11. The method according to claim 10 wherein the dilution of the Botulinum toxin is about 1 cc normal saline per 100 units of Botulinum toxin.
 12. The method according to claim 11 wherein the Botulinum toxin is Botulinum toxin A.
 13. The method according to claim 12 wherein the Botulinum toxin A is onabotulinumtoxin A.
 14. A method for treating a human with migraine headache comprising administering a therapeutically effective amount of onabotulinumtoxin A, at a dilution of about 1 cc normal saline per 100 units of onabotulinumtoxin A, by extramuscular injection into one or more of the greater palatine foramen, the lesser palatine foramen and the incisive foramen.
 15. The method of claim 1 wherein administration comprises intraoral extramuscular injection to either the region of the mucobuccal fold at the maxillary second molar or through the greater palatine canal located between the second and third molars approximately 7 mm from the end of the hard palate. 